3-aza-a-homo-steroids

ABSTRACT

COMPOUNDS OF THE FORMULA:   2-(O=),5A-R&#34;,12-R,8-(CH3-CO-),8-(R&#39;&#39;-OOC-),7A-CH3-2,3,4,5,   5A,5B,6,7,10A,10B-DECAHYDROCYCLOPENTA(5,6)NAPHTH(1,2-D)-   AZEPINE   WHEREIN R IS HYDROGEN, METHYL, EHTYL, CHLORINE, BROMINE OR FLUORINE R&#39;&#39; IS HYDROGEN OR ALKYL FROM 1 TO 11 CARBON ATOMS AND R&#34; IS HYDROGEN OR METHYL, ARE POTENT PROGESTATIONAL AGENTS AND POSSESS ANTI-OVULATORY ACTIVITY.

United States Par 01 fle 3,679,664 Patented July 25, 1972 4 Claims ABSTRACT OF THE DISCLOSURE Compounds of the formula:

wherein R is hydrogen, methyl, ethyl, chlorine, bromine or fluorine, R is hydrogen or alkyl from 1 to 11 carbon atoms and R" is hydrogen or methyl, are potent progestational agents and possess anti-ovulatory activity.

This is a division of application Ser. No. 465,175 filed June 18, 1965, now abandoned.

The present invention relates to steroidal 3-oximes and 3-aza-A-homo steroids. Specifically, the new compounds may be represented by the following structural formulae:

HON

wherein R is hydrogen, methyl, ethyl, chlorine, bromine or fluorine, R is hydrogen or alkyl from 1 to 11 carbon atoms and R" is hydrogen or methyl.

The 3-oximes and 3-aza compounds of the present invention are potent progestational agents and more particularly possess anti-ovulatory activity.

Steroidal oximes can conventionally be prepared by reaction of a carbonyl group on the steroid with a hydroxylamine salt in the presence of a base such as pyridine, sodium hydroxide or sodium acetate.

When a steroid having a carbonyl group at the 3- and 20-positions is subjected to treatment With a hydroxylamine salt under basic conditions, the dioxine would be the expected product. Due to the presence of a l7-ester group in the starting compoundsfrorn which the oximes of this invention are prepared, steric hindrance prevents the oximation of the ZO-carbonyl. The 17-ester can be readily converted to the alcohol by hydrolysis.

The oxime is subjected to Beckmann rearrangement in the presence of an acidic reagent to form the corresponding 3-aza-A-homo steroid. Typical acidic reagents which may be used are thionyl chloride, polyphosphoric acid, p-toluenesulfonyl chloride, p-acetylaminobenzene-sulfonyl chloride, p-aminobenzenesulfonyl chloride and phosphorus pentachloride.

As starting materials for the preparation of the oximes there are used compounds of the structural formula wherein R is hydrogen, methyl, ethyl, chlorine, bromine or fluorine, R is alkyl from 1 to 11 carbon atoms, and R" is hydrogen or methyl.

The following examples illustrate the invention:

EXAMPLE I 17u-acetoxypregn-4,6-diene-3,20-dione 3-oxime 17a-acetoxy-6-dehydro-progesterone (4.5 g.) is treated with 30 ml. of methanol, 2.0 ml. of pyridine and 1.0 g. of hydroxylamine hydrochloride. The mixture is heated on a steam-bath for one-half hour and allowed to cool. The precipitates are filtered and recrystallized from methanol to give l7a-acetoxypregn-4,6-diene-3,ZO-dione 3- oxime, M.P. 247-250.

Analysis.-Calculated for C H NO (percent): C, 71.66; H, 8.11; N, 3.63. Found (percent): C, 71.79; H, 8.33; N,3.36.

EXAMPLE II 6-chloro-17a-acetoxypregn-4,6-diene-3,20-dione 3-oxime One and a half gram of 6-chloro-17a-acetoxypregn-4,6- diene-3,20-dione is treated with 25 ml. of methanol, 500 mg. of hydroxylamine hydrochloride and 500 mg. of sodium acetate. The mixture is heated on a steam bath for one-half hour and allowed to cool. The crystals are filtered and recrystallized from methanol to give 6-chloro- 17a acetoxypregn 4,6 diene 3,20 dione 3-oxime, M.P. 166-168".

Analysis.-Calculated for C H NO Cl (percent): C, 65.79; H, 7.20; N, 3.34. Found (percent): C, 65.65; H, 7.33; N, 3.33.

EXAMPLE 1H 6-methyl-17a-acetoxypregn-4,6-diene-3,20-dione 3-oxime One gram of 6-methyl-17u-acetoxypregn-4,6-diene-3,20- dione is dissolved in 15 ml. of pyridine containing 250 mg. of hydroxylamine hydrochloride. The flask is heated on a steam-bath for one-half hour and poured over a large excess of ice-water. The solid material is collected by filtration and recrystallized from methanol to give 6- 3 methyl 17a acetoxypregn 4,6 diene 3,20 dione 3-oxime, M.P. 225-227.

Analysis.Calculated for C H NO (percent) C, 72.15; H, 8.33; W, 3.51. Found (percent): C, 72.40; H, 8.40; N, 3.58.

Following the procedure of Examples I to III, the following related compounds are prepared starting from the appropriate ketone:

dione 3 oxime.

EXAMPLE IV 3-aza-17a-acetoxy-A-homopregn-4a,6-diene-4,20-dione 17 acetoxypregn-4,6-diene-3,ZO-dione 3-oxime (1.2 g.) is treated with 10 ml. of dioxane and 1.0 ml. of thionyl chloride. The mixture is stirred for one and one-half hours and poured over ice-water. The solid material is extracted with ethyl acetate. The organic layer is washed with water until neutral to litmus, dried over sodium sulfate and evaporated. The semi-solid residue is recrystallized from acetone-hexane to give 3-aza-17a-acetoxy-A-homopregn- 4a-6-diene, -4,20-dione, M.P. 206210.

Analysis.Calculated for C H NO (percent): C, 71.66; H, 8.11; N, 3.63. Found (percent): C, 71.43; H, 8.20; N, 3.81.

EXAMPLE V v 3-aza-6-chloro-l7a-acetoxy-A-homopregn-4a,G-diene- 4,20-dione One gram of 6-chloro-17a-acetoxypregn-4,6-diene-3,20- dione 3-oxime is treated with 5.7 g. of polyphosphoric acid and maintained between 50-60 for one hour. The mixture is recomposed with ice-water and extracted with methylene chloride. The organic layer is further washed with water until neutral to litmus, dried over sodium sulfate and evaporated. The brown residue is crystallised from hexane-benzene followed by recrystallization from acetone-hexane to give 3-aza-6-chloro-17a-acetoxy-A-homopregn-4a,6-diene-4,20-dione, M.P. 140142.

Analysis.Ca1culated for C H NO Cl (percent): C,

65.79; H, 7.20; N, 3.34. Found (percent): C, 65.55; H,

EXAMPLE VI 3-aza-6-methy1-17a-acetoxy-A-homopregn-4a,6- diene- 4,20-dione One gram of 6-methyl-17a-acetoxypregn-4,6-diene-3,20- dione 3-oxime is dissolved in 20 ml. of dioxane and treated with 0.7 ml. of thionyl chloride. The mixture is stirred for 2 hours and decomposed with a large amount of icewater. It is extracted with methylene chloride and the organic layer is washed with potassium bicarbonate solution followed by water until neutral to litmus. It is dried over sodium sulfate and evaporated to give a semi-solid which is recrystallized from benzene-hexane to give 3-aza- 4 6 methyl-l7a-acetoxy-A-homopregn 4a,6 dione, M.P. 138-140.

Analysis.-Calculated for- C H NO (percent): C, 72.15; H, 8.33; N, 3.51. Found (percent): C, 71.62; H, 8.53; N, 3.19.

Following the procedure of Examples IVQto VI, the following related compounds are prepared starting from th appropriate 3-oxime:

3-aza-6-ethyl-l7a-acetoxy-A-homopregn-4a,6-diene- 4,20-dione,

3-aza-19-nor-6-ethyl-l7a-acetoxy-A-homopregn-4a,6-

diene-4,20-dione,

dime-4,20-

. 3 aza 19 nor-17a-acetoxy-A-homopregn-4u,6-diene- 4,20-dione, I

3-aza-19-n0r-6-chloro-17a-acetoxy-A-homopregn-4a,6

diene-4,20-dione,

3-aza-19-nor-6-methyl-17a-acetoxy-A-homopregn-4a,6-

diene-4,20-dione,

i 3-aza-6-fluoro-17e-caproxy-A-homopregm4a,6-diene- 4,20-dione, 3-aza-19-nor-6-fluoro-17a-caproxy-A-homopregn-4a,6-

diene-4,20-dione, 3-aza-17a-undecyloxy-A-homopren 4a,6-diene- 4,20-dione, 3-aza-19-nor-17a-undecyloxy-A-homopregn-4a,6-diene- 4,20-dione, 3-aza-6-methyl-17u-undecyloxy-A-homopregn-4a,6-

diene-4,20-dione, and 3-aza-19-nor-6-methyl-17a-undecyloxy-A-homopregn- 4a,6-diene-4,20-dione.

What is claimed is: 1. A compound of the formula wherein R is selected from the group consisting of hydrogen, methyl, ethyl, chlorine, bromine and fluorine, R is selected from the group consisting of hydrogen and alkyl of from 1 to 11 carbon atoms and R" is selected from the group consisting of hydrogen and methyl.

2. 3-aza 17 acetoxy-A-homopregn-4a,6-diene-4,20- dione.

3. 3-aza -6a methyl-17a-acetoxy-A-homopregn-4a,6- diene-4,2O-dione.

4. 3 aza 6 chloro-17a-acetoxy-A-homopregn-4a,6- diene-4,20-dione.

References Cited UNITED STATES PATENTS 6/1964 Ringold 260239.55 7/ 1969 Shrolf 260-239.3

OTHER REFERENCES Ellis et al.: J. Chem. Soc. (1960), pp. 2828-2833. Shoppee et al.: J. Chem. Soc. (1961), pp. 3641-3645.,

HENRY R. JILES, Primary Examiner R. I. BOND, Assistant Examiner US. Cl. X.R.

mg UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 79, Dated July 25,1972

Inventor(s) Arvin P. ShIOff It is certified that error appears in the above-identified patent v and that said Letters Patent are hereby corrected as shown below:

"I I- .In Column 3, line 18, "6-ethyl-l7aacetoxypr*egnt,

should read 6-'f1.uorolTa-caproxypregn-H In Column 3, line #9, "is reoomposed'" should read is decomposed Signed and sealed this 13th day of February 1973.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents 

